Dystonia Related Research

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Dystonia-related Research at the National Primate Research Center and the University of Wisconsin Hospital and Clinics

Erwin B. Montgomery, M.D.

November 29, 2005

The discovery of genetic abnormalities causing some forms of dystonia is very encouraging. As the functions of these genes are understood, it may be possible to develop treatments to prevent or slow the progression of dystonia. Even those patients with dystonia for whom the cause is unknown may still benefit. As is being discovered in Alzheimer’s and Parkinson’s disease research, different genetic abnormalities seem to share common mechanisms and these mechanisms may be relevant to those without the genetic abnormalities.

Unfortunately, it will probably be a long time from now before treatments based on genetic abnormalities will help relieve the symptoms and disabilities of those with advanced dystonia. For example, we know that just replacing the dopamine neurons that have been lost in Parkinson’s disease has not been helpful to those with advanced disease. Consequently, we have an obligation to develop treatments that will help those whose disease is causing suffering and disability and do so quickly.

It is also unfortunate that we do not have an animal model of dystonia. Parkinson’s disease research was greatly advanced with the discovery that a neurotoxin called MPTP could produce Parkinsonism in laboratory animals. Parkinson’s disease patients now are benefiting from research in MPTP-treated laboratory animals. However, the recent development of Deep Brain Stimulation (DBS) for dystonia provides a great opportunity to understand what goes wrong in the brain in those with dystonia.

DBS is standard accepted FDA approved therapy for patients with dystonia who have failed medication or botulinum toxin injection treatments. The DBS electrode is implanted in the globus pallidus interna in the brain. Constant pulses of electricity are delivered to the globus pallidus interna. DBS surgery now provides an opportunity to understand the brain mechanisms that may go wrong and cause the symptoms and disabilities of dystonia. First, during surgery and prior to implantation of the permanent stimulating electrodes, a temporary electrode with a microscopic tip is placed into the brain. This microelectrode can record electrical impulses generated by individual neurons in the globus pallidus interna. Neurons communicate and relay instructions by pulses of electrical energy that can be recorded by the microelectrodes. In this way, physicians and scientists can eavesdrop on the conversations among the neurons. This way we can see how neurons in the globus pallidus interna of dystonia patients are misbehaving and this could lead to ways to reverse this abnormality and thereby, restore normal function.

DBS provides another opportunity to study what goes wrong in the brain with dystonia. We can record brain wave activity through the permanent DBS electrodes. WE can correlate changes in the brain wave activity with the patient’s movements. Also, we can stimulate in different patterns and determine what is it about the DBS that is most effective in controlling the symptoms of dystonia. This could lead to better treatments in the future.

However, there are important questions about how DBS affects the basal ganglia of which the globus pallidus interna is part that cannot be answered effectively in humans with dystonia. To answer these questions, we must conduct experiments in laboratory animals, particularly non-human primates. In animals, we can place any number of recording and stimulating electrodes, which is not the case during human surgery. Further, we can conduct these experiments over many months, which we cannot do with humans.

For the last several years we have been studying how neurons in the basal ganglia respond to DBS. One of our most important discoveries is that we have to significantly re-think our old notions about how the basal ganglia works and how it might be affected in disease. Consequently, we now have to address very basic questions about how the basal ganglia functions normally so that we can interpret the results of the DBS research. Also, comparing our better understanding of how neurons in the brain normally function to recording in humans with dystonia, we will be in a better position to understand what the neuronal recordings from human dystonia patients undergoing DBS are telling us about how the brain misbehaves.

The opportunity to combine human and animal research at the University of Wisconsin provides great advantages. Observations gained from human DBS can be rapidly explored in the animal. Insights gained from studies of animals can be rapidly applied to humans. Many of the instruments, techniques, computer programs, and analyses methods developed in the animal lab also facilitate research in the human operating room and clinic. For example, methods for microelectrode recordings developed in the animal laboratories are now being applied in human operations to make the surgery safer and more effective.

My mom and I wanted to thank you for hosting such a great symposium this year. This was our third year and we are looking forward to next years. E. Mathews